Herpes simplex virus type 1 (HSV-1) causes a variety of illness, ranging in severity from relatively benign cold-sores to fatal encephalitis. In addition, some studies have suggested a link between antecedent HSV-1 infection of the central nervous system (CNS) with the anosmia associated with psychiatric disorders, Parkinson's disease, and dementia. However, because the relationship between HSV-1 infection of the olfactory and trigeminal systems of the CNS and anosmia has not been thoroughly studied, it remains uncertain whether HSV-1 infection causes olfactory disorders. Establishing a link between HSV-1 infection and olfactory dysfunction is further complicated by the fact that HSV-1 strains vary considerably in their ability to infect and travel within the CNS olfactory and trigeminal systems. In this application, animal models of acute and reactivated HSV-1 infection of the CNS will be studied to develop a more thorough understanding of the effects of HSV-1 infection on the CNS olfactory system. Two prototype virulent HSV-1 strains have been identified which induce quite different clinical outcomes following intranasal infection. The clinical consequence of infection by these strains is apparently based on their differential ability to damage specific centers within the CNS olfactory system and its forebrain connections. The hypothesis to be tested in this proposal is that the clinical and pathological consequences of HSV-1 infection is dependent on viral tropism for specific CNS olfactory centers. In the first specific aim, the precise sites where the prototype HSV-1 strains replicate will be determined by histopathological, immunohistochemical, and in situ hybridization techniques. The effect of virus replication on the metabolism of olfactory system neurons will also be studied. In the second and third specific aims, the viral genetic elements which enable the prototype HSV-1 strains to home to, and replicate within, specific CNS olfactory centers will be defined through the construction and testing of intertypic recombinant viruses. In the fourth and fifth specific aims, more precise mapping of the genes of the prototype HSV-1 strains which encode specific tropism and virulence for CNS olfactory centers will be undertaken. Together, these studies will define the viral genetic elements which control the tropism and virulence of HSV-1 for olfactory and trigeminal system neurons, and will form the experimental and theoretical basis for further studies of olfactory deficits associated with HSV-1 infection in man.